This invention relates to methods for extended treatment of an ocular condition. In particular the present invention releases to methods for extended treatment of an ocular condition with an intraocular implant.
An ocular condition can include an inflammatory, neoplastic, infectious, vascular, neovascular and/or degenerative disease, ailment or condition which affects or involves the eye or one of the parts or regions of the eye. Broadly speaking the eye includes the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles (such as the oblique and rectus muscles) and the portion of the optic nerve which is within or adjacent to the eyeball. An anterior ocular condition is a disease, ailment or condition which affects or which involves an anterior (i.e. front of the eye) ocular region, location or site (hereafter an ocular site), such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles. Thus, an anterior ocular condition primarily affects or involves, the conjunctiva, the cornea, the anterior chamber, the iris, the posterior chamber (behind the iris but in front of the posterior wall of the lens capsule), the lens or the lens capsule and blood vessels and nerve which vascularize or innervate an anterior ocular region or site. A posterior ocular condition is a disease, ailment or condition which primarily affects or involves a posterior ocular site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (including the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular site.
Thus, a posterior ocular condition can include a disease, ailment or condition, such as for example, macular degeneration (such as non-exudative age related macular degeneration and exudative age related macular degeneration); macular hole; light, radiation or thermal damage to a posterior ocular tissue; choroidal neovascularization; acute macular neuroretinopathy; macular edema (such as cystoid macular edema and diabetic macular edema); Behcet's disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy); retinal arterial occlusive disease; central retinal vein occlusion; uveitic retinal disease; retinal detachment; ocular trauma which affects a posterior ocular site; a posterior ocular condition caused by or influenced by an ocular laser treatment; posterior ocular conditions caused by or influenced by a photodynamic therapy; photocoagulation; radiation retinopathy; epiretinal membrane disorders; branch retinal vein occlusion; anterior ischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa and glaucoma. Glaucoma can be considered a posterior ocular condition because the therapeutic goal is to prevent the loss of or reduce the occurrence of loss of vision due to damage to or loss of retinal cells or retinal ganglion cells (i.e. neuroprotection).
An anterior ocular condition can include a disease, ailment or condition, such as for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; hyperopia; pupil disorders; refractive disorders and strabismus. Glaucoma can also be considered to be an anterior ocular condition because a clinical goal of glaucoma treatment can be to reduce a hypertension of aqueous fluid in the anterior chamber of the eye (i.e. reduce intraocular pressure).
The present invention is directed to a method for providing an extended treatment of an ocular condition, such as an anterior ocular condition or a posterior ocular condition or to an ocular condition which can be characterized as both an anterior ocular condition and a posterior ocular condition.
Therapeutic compounds useful for the treatment of an ocular condition can include cytokines and active agents with, for example, an anti-neoplastic (i.e. anti-cancer), anti-angiogenesis, kinase inhibition, anticholinergic, anti-adrenergic and/or anti-inflammatory activity.
Macular degeneration, such as age related macular degeneration (“AMD”) is a leading cause of irreversible vision loss in elderly populations. It is estimated that thirteen million Americans have evidence of macular degeneration. Macular degeneration results in a break down or injury to the macula, the central part of the retina responsible for the sharp, direct vision needed to read or drive. Central vision is especially or selectively affected. Macular degeneration is diagnosed as either dry or wet (exudative). The dry form of macular degeneration is more common than the wet form of macular degeneration, with about 90% of AMD patients being diagnosed with dry AMD. The wet form of the disease usually leads to more rapid and more serious vision loss. Macular degeneration can produce a slow or sudden painless loss of vision. The cause of macular degeneration is not clear. The dry form of AMD may result in thinning of macular tissues, depositing of pigment in the macula, or a combination of the two processes. With wet AMD, new blood vessels grow within and beneath the retina and leak blood and fluid. This leakage causes injury to retinal cells and creates blind spots in central vision.
Macular edema (ME) can result in a swelling or thickening of the macular and appears to be a nonspecific response of the retina to a variety of insults. Thus, ME is associated with a number of diseases, including anterior or posterior uveitis, retinal vascular abnormalities (diabetic retinopathy and retinal venous occlusive disease), as a sequela of cataract surgery (Irvine-Gass Syndrome), macular degeneration, vitreo-macular traction syndrome, inherited or acquired retinal degeneration, eye inflammation, idiopathic central serous chorioretinopathy, pars planitis, retinitis pigmentosa, radiation retinopathy, posterior vitreous detachment, epiretinal membrane formation, idiopathic juxtafoveal retinal telangiectasia, following Nd:YAG capsulotomy or iridotomy. Some patients with ME may have a history of use of topical epinephrine or prostaglandin analogs for glaucoma. Macular edema involves the development of microangiopathy, characterized by abnormal retinal vessel permeability and capillary leakage into the adjacent retinal tissues. The macula becomes thickened due to accumulation of fluid which leaks out of weak blood vessel walls due to a breakdown of the inner blood-retinal barrier at the level of the capillary endothelium, often resulting in significant disturbances in visual acuity. The blood and fluid leaks out of the weak vessel walls into a very small area of the macula which is rich in cones, the photoreceptors that detect color and from which daytime vision depends. Blurring then occurs in the middle or just to the side of the central visual field. Visual loss can progress over a period of years. Symptoms of ME include blurred central vision, distorted vision, vision tinted pink and light sensitivity.
In some cases macular edema can resolves spontaneously or with show remission after a short-term treatment. However, in cases of persistent macular edema (PME), visual loss continues to be a significant therapeutic challenge. Therapies for macular edema utilize a stepwise approach including surgical and medical methods. A first line of treatment for certain types of ME can be anti-inflammatory drops topically applied. Currently there are no approved therapies for the treatment of PME. Macular edema that has failed to respond to drug therapy and laser photocoagulation represents a significant unmet medical need.
Drug therapy for macular edema can include topical, periocular, subconjunctival/intravitreal, or systemic corticosteroids; topical and systemic nonsteroidal anti-inflammatory agents (NSAIDs); and/or immunosuppressants. Nonetheless, with variable incidence, macular edema can persist regardless of treatment or causation resulting in severe vision loss. Liquid, intravitreal triamcinolone acetonide (available from Bristol Myers Squibb under the tradename Kenalog-40®) injection has been used to treat ocular inflammation and macula edema. Kenalog-40® is a suspension triamcinolone acetonide (40 mg/mL) formulated with sodium chloride for isotonicity, 0.9% (w/v) benzyl alcohol as preservative, 0.75% carboxymethylcellulose sodium, and 0.04%, polysorbate 80. It is approved for intramuscular depot delivery for the treatment of inflammation and has been used intravitreally to treat ocular inflammation as well as macular edema due to numerous causes. Unfortunately, side-effects including elevated intraocular pressure, cataract, endophthalmitis (such as infectious endophthalmitis and sterile endophthalmitis), retinal toxicity and crystalline retinal deposits have been reported from clinical use of intravitreal triamcinolone acetonide.
Surgical methods for the treatment of macular edema including laser photocoagulation have had mixed results. Focal/grid laser photocoagulation for the prevention of moderate visual loss has been shown to be efficacious in diabetic retinopathy and branch retinal vein occlusion patients, but not in central retinal vein occlusion patients. As a last resort, a vitrectomy is sometimes performed in patients who have persistent macular edema that has failed to respond to less invasive treatments.
Dexamethasone, a potent anti-inflammatory in the corticosteroid family, has been shown to suppress inflammation by inhibiting edema, fibrin deposition, capillary deposition and phagocytic migration of the inflammatory response. Corticosteroids prevent the release of prostaglandins which have been identified as one of the causative agents of cystoid macular edema. Additionally, corticosteroids including dexamethasone have also been shown to have potent anti-permeability activity by inhibiting the synthesis of VEGF. Despite known anti-inflammatory and anti-permeability properties, use of corticosteroid in the treatment of macular edema has been limited because of the inability to deliver and to maintain adequate quantities of the drugs at the macular without resultant toxicities.
Previously, dexamethasone use has yielded varying degrees of success in treating retinal disorders including macular edema largely due to the inability to deliver and maintain adequate quantities of the drug to the posterior segment (vitreous) without resultant toxicities. Topical administration of 1 drop (50 μl) of a 0.1% dexamethasone ophthalmic suspension, 4 times a day is equivalent to approximately 200 μg per day, however, only about 1% (2 μg per day) reaches the anterior segment, and only a fraction of that amount moves into the posterior segment (vitreous). Although intravitreal injections of dexamethasone have been used, the exposure of the drug is very temporal as the half-life of the drug within the eye is approximately 3 hours, Periocular and posterior sub-Tenon's injections of dexamethasone have been used, but with only short-term treatment effect.
Treatment with corticosteroids must be monitored closely due to potential toxicity and long-term side effects. Adverse reactions listed for conventional ophthalmic dexamethasone preparations include: glaucoma (with optic nerve damage, visual acuity and field defects), posterior subcapsular cataract formation, and secondary ocular infection from pathogens including herpes simplex. Systemic doses of dexamethasone can be as high as 9000 μg/kg/day, of which only a small portion reaches the posterior segment, and may be associated with additional hazardous side-effects including hypertension, hyperglycemia, increased susceptibility to infection, and peptic ulcers.
Although an efficient means of delivering a drug to the posterior segment is direct delivery into the vitreous body, the natural pharmacokinetics of the eye typically result in a short half-life unless the drug can be delivered using a formulation capable of providing sustained release. By delivering a drug intravitreally, the blood-eye barrier is circumvented and intraocular therapeutic levels can be achieved without the risk of systemic toxicity.
An anti-inflammatory (i.e. immunosuppressive) agent can be used for the treatment of an ocular condition which involves inflammation, such as an uveitis or macula edema. Thus, topical or oral glucocorticoids have been used to treat uveitis. A major problem with topical and oral drug administration is the inability of the drug to achieve an adequate (i.e. therapeutic) intraocular concentration. See e.g. Bloch-Michel E. (1992). Opening address: intermediate uveitis, In Intermediate Uveitis, Dev. Ophthalmol, W. R. F. Böke et al. editors., Basel: Karger, 23:1-2; Pinar, V., et al. (1997). Intraocular inflammation and uveitis” In Basic and Clinical Science Course. Section 9 (1997-1998) San Francisco: American Academy of Ophthalmology, pp. 57-80, 102-103, 152-156; Böke, W. (1992). Clinical picture of intermediate uveitis, In Intermediate Uveitis, Dev. Ophthalmol. W. R. F. Böke et al. editors., Basel: Karger, 23:20-7; and Cheng C-K et al. (1995). Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis, Invest. Ophthalmol. Vis. Sci. 36:442-53.
Systemic glucocorticoid administration can be used alone or in addition to topical glucocorticoids for the treatment of uveitis. However, prolonged exposure to high plasma concentrations (administration of prednisone 1 mg/kg/day for 2-3 weeks) of steroid is often necessary so that therapeutic levels can be achieved in the eye.
Unfortunately, these high drug plasma levels commonly lead to systemic side effects such as hypertension, hyperglycemia, increased susceptibility to infection, peptic ulcers, psychosis, and other complications. Cheng C-K et al. (1995). Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis, Invest. Ophthalmol. Vis. Sci. 36:442-53; Schwartz, B. (1966). The response of ocular pressure to corticosteroids, Ophthalmol. Clin. North Am. 6:929-89; Skalka, H. W. et al. (1980). Effect of corticosteroids on cataract formation, Arch Ophthalmol 98:1773-7; and Renfro, L. et al. (1992). Ocular effects of topical and systemic steroids, Dermatologic Clinics 10:505-12.
Additionally, delivery to the eye of a therapeutic amount of an active agent can be difficult, if not impossible, for drugs with short plasma half-lives since the exposure of the drug to intraocular tissues is limited. Therefore, a more efficient way of delivering a drug to treat a posterior ocular condition is to place the drug directly in the eye, such as directly into the vitreous. Maurice, D. M. (1983). Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Lee, V. H. L. et al. (1989). Drug delivery to the posterior segment” Chapter 25 In Retina. T. E. Ogden and A. P. Schachat eds., St. Louis: C V Mosby, Vol. 1, pp. 483-98; and Olsen, T. W. et al. (1995). Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903.
Techniques such as intravitreal injection of a drug have shown promising results, but due to the short intraocular half-life of active agent, such as the glucocorticoid dexamethasone (approximately 3 hours), intravitreal injections must be frequently repeated to maintain a therapeutic drug level. In turn, this repetitive process increases the potential for side effects such as retinal detachment, endophthalmitis, and cataracts. Maurice, D. M. (1983). Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Olsen, T. W. et al. (1995). Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903; and Kwak, H. W. and D'Amico, D. J. (1992). Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection, Arch. Ophthalmol. 110:259-66.
Additionally, topical, systemic, and periocular glucocorticoid treatment must be monitored closely due to toxicity and the long-term side effects associated with chronic systemic drug exposure sequelae. Rao, N. A. et al. (1997). Intraocular inflammation and uveitis, In Basic and Clinical Science Course. Section 9 (1997-1998) San Francisco: American Academy of Ophthalmology, pp. 57-80, 102-103, 152-156; Schwartz, B. (1966). The response of ocular pressure to corticosteroids, Ophthalmol Clin North Am 6:929-89; Skalka, H. W. and Pichal, J. T. (1980). Effect of corticosteroids on cataract formation, Arch Ophthalmol 98:1773-7; Renfro, L and Snow, J. S. (1992). Ocular effects of topical and systemic steroids, Dermatologic Clinics 10:505-12; Bodor, N. et al. (1992). A comparison of intraocular pressure elevating activity of loteprednol etabonate and dexamethasone in rabbits, Current Eye Research 11:525-30.
U.S. Pat. No. 6,217,895 discusses a method of administering a corticosteroid to the posterior segment of the eye, but does not disclose a bioerodible implant.
U.S. Pat. No. 5,501,856 discloses controlled release pharmaceutical preparations for intraocular implants to be applied to the interior of the eye after a surgical operation for disorders in retina/vitreous body or for glaucoma.
U.S. Pat. No. 5,869,079 discloses combinations of hydrophilic and hydrophobic entities in a biodegradable sustained release implant, and describes a polylactic acid polyglycolic acid (PLGA) copolymer implant comprising dexamethasone. As shown by in vitro testing of the drug release kinetics, the 100-120 μg 50/50 PLGA/dexamethasone implant disclosed did not show appreciable drug release until the beginning of the fourth week, unless a release enhancer, such as HPMC was added to the formulation.
U.S. Pat. No. 5,824,072 discloses implants for introduction into a suprachoroidal space or an avascular region of the eye, and describes a methylcellulose (i.e. non-biodegradable) implant comprising dexamethasone. WO 9513765 discloses implants comprising active agents for introduction into a suprachoroidal or an avascular region of an eye for therapeutic purposes.
U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose biodegradable ocular implants comprising microencapsulated drugs, and describes implanting microcapsules comprising hydrocortisone succinate into the posterior segment of the eye.
U.S. Pat. No. 5,164,188 discloses encapsulated agents for introduction into the suprachoroid of the eye, and describes placing microcapsules and plaques comprising hydrocortisone into the pars plana. U.S. Pat. Nos. 5,443,505 and 5,766,242 disclose implants comprising active agents for introduction into a suprachoroidal space or an avascular region of the eye, and describes placing microcapsules and plaques comprising hydrocortisone into the pars plana.
Zhou et al. disclose a multiple-drug implant comprising 5-fluorouridine, triamcinolone, and human recombinant tissue plasminogen activator for intraocular management of proliferative vitreoretinopathy (PVR). Zhou, T, et al. (1998). Development of a multiple-drug delivery implant for intraocular management of proliferative vitreoretinopathy, Journal of Controlled Release 55: 281-295.
U.S. Pat. No. 6,046,187 discusses methods and compositions for modulating local anesthetic by administering one or more glucocorticosteroid agents before, simultaneously with or after the administration of a local anesthetic at a site in a patient.
U.S. Pat. No. 3,986,510 discusses ocular inserts having one or more inner reservoirs of a drug formulation confined within a bioerodible drug release rate controlling material of a shape adapted for insertion and retention in the “sac of the eye,” which is indicated as being bounded by the surfaces of the bulbar conjunctiva of the sclera of the eyeball and the palpebral conjunctiva of the eyelid, or for placement over the corneal section of the eye.
U.S. Pat. No. 6,369,116 discusses an implant with a release modifier inserted within a scleral flap.
EP 0 654256 discusses use of a scleral plug after surgery on a vitreous body, for plugging an incision.
U.S. Pat. No. 4,863,457 discusses the use of a bioerodible implant to prevent failure of glaucoma filtration surgery by positioning the implant either in the subconjunctival region between the conjunctival membrane overlying it and the sclera beneath it or within the sclera itself within a partial thickness sclera flap.
EP 488 401 discusses intraocular implants, made of certain polylactic acids, to be applied to the interior of the eye after a surgical operation for disorders of the retina/vitreous body or for glaucoma.
EP 430539 discusses use of a bioerodible implant which is inserted in the suprachoroid.
Significantly, it is known that PLGA co-polymer formulations of a bioerodible polymer comprising an active agent typically release the active agent with a characteristic sigmoidal release profile (as viewed as time vs percent of total active agent released), that is after a relatively long initial lag period (the first release phase) when little if any active agent is released, there is a high positive slope period when most of the active agent is released (the second release phase) followed by another near horizontal (third) release phase, when the drug release reaches a plateau.
Thus, there is a need for a extended therapeutic treatment of an ocular condition, such as posterior ocular condition. In particular, there is a need for treatment over an extended duration, for example, time periods extending up to 60 days, 90 days, 120 days, 6 months, 8 months, 12 months or more, after release of a therapeutic amount of a drug at an ocular site, such as the vitreous. Such extended treatment with an active agent can be advantageous to prevent recurrence of the inflammatory or other posterior ocular condition treated. It can also minimize the number of surgical interventions required by the patient over time to treat an ocular condition.